Substituted thienodiazepines

ABSTRACT

5-Substituted-phenyl-thienodiazepines bearing a halogen or nitro substituent on the thieno ring are disclosed together with processes for their preparation and novel intermediates employed in these processes. These novel thienodiazepines are useful as muscle relaxants and sedatives.

tates Hromatka et a1.

atent 1 51 Mar. 18, 1975 I SUBSTITUTED THIENODIAZEPINES [75] Inventors:Otto Hromatka; Dieter Binder, both of Vienna, Austria [73] Assignee:Hoffman-La Roche Inc., Nutley,

[22] Filed: May 5, 1972 [21] App]. No.: 250,701

[30] Foreign Application Priority Data May 14, 1971 Switzerland 7303/71Mar. 29, 1972 Switzerland 4664/72 [52] US. Cl..... 260/239.3 T,260/3322, 260/332.3, 424/244, 424/275 FOREIGN PATENTS OR APPLICATIONS1,961,727 9/1970 Germany 260/2393 B 2,107,356 8/1971 Germany 260/2393 BOTHER PUBLICATIONS Yale J. Med. and Pharm. Chem. Vol. 1, No. 2, pages121-133 (1959) Zbinden et a1. Advances in Pharmacology Vol. 5 pages250-261 (Academic Press) (1967) Sternbach et a]. Some Aspects ofStructure-Activity Relationship in Psychotripic Agents of the 1,4-Benzodiazepine Series A Symmposium Held at the Regional ResearchLaboratory, Hyder Bad, India, CSIR New Delhi, India (1966) PrimaryExaminer-Henry R. Jiles Assistant ExaminerRobert T. Bond Attorney,Agent, or Firm-Samuel L. Welt; Bernard 5. Leon; Frank P. Hoffman [57]ABSTRACT 5-Substituted-phenyl-thienodiazepines bearing a halogen ornitro substituent on the thieno ring are disclosed together withprocesses for their preparation and novel intermediates employed inthese processes. These novel thienodiazepines are useful as musclerelaxants and sedatives.

4 Claims, N0 Drawings SUBSTITUTED THIENODIAZEPINES DETAILED DESCRIPTIONOF THE INVENTION The present invention relates to diazepine derivatives.More particularly, the present invention relates tothienosubstituted-thienodiazepine derivatives and to processes forpreparing the foregoing.

The thienodiazepine derivatives of the present invention are of theformula wherein R represents halogen or nitro, R represents hydrogen orCH -X wherein X represents hydrogen, lower alkyl, lower alkenyl, C -Ccycloalkyl, hydroxymethyl, methoxy or a dilower alkylamino lower alkylgroup containing no more than 5 carbon atoms and R representso-halophenyl, o-trifluoromethylphenyl, 0,0-dihalophenyl and onitrophenylprovided however that when R is nitro, R is other than an o-nitrophenylgroup, and the salts thereof, preferably pharmaceutically acceptableaddition salts thereof.

As used herein, either alone or in combination with another radical, theterm lower alkyl refers to straight or branched chain saturatedhydrocarbon groups containing 1-4 carbon atoms. Ther term lower alkenylas used herein refers to straight or branched chain hydrocarbon groupswhich contain an olefinic double bond and no more than 4 carbon atoms.Unless expressly stated otherwise, the term halogen is intended toencompass all four halogens, i.e. fluorine, chlorine, bromine andiodine.

When R represents a halogen atom, chlorine, bromine and iodine arepreferred with chlorine being particularly preferred. When R representso-halophenyl, the groupings o-fluorophenyl and o-chlorophenyl arepreferred. When R represents an o,o-dihalophenyl group, the halogenatoms are preferably the same, with o,o'-difluorophenyl being especiallypreferred. R pref erahly represents hydrogen, methyl allyl,eyclopropylmethyl, hydroxyethyl, methoxymethyl or 2 dicthylaminoethyl. Rin the most preferred aspect is hydrogen or methyl.

A particularly preferred compound encompassed by the formula I above is:

7-chlorol ,3-dihydro-5-( o-nitrophenyl )-2H-thieno[2,3-e][1,4]diazepin-2-one. Included among the other preferred compoundsof the formula I are: 5-(o-chlorophenyl l ,3-dihydro-7-iodo-2H-thieno[2,3-e][ l ,4]diazepin-2-one; 7-chloro-5-(o-fluorophenyl l,3-dihydro-2H-thieno- I2,3-e][ l ,4]diazepin-2-one;7-chloro-5-(2,6-difluorophenyl)-l,3-dihydro-2H- thieno-[2,3-e][ l,4]diazepine-2-onc; 7-ehloro-l,3-dihydro-l-methyl-5-(o-nitrophenyl) -2-H-thienol 2,3-e][ l,4]diazepin-2-one;

5-(o-chlorophenyl)-l,3-dihydro-7iodo-l-methyl -2- H-thieno[ [2,3-e][ l,4]diazepin-2-one;

5-(o-chlorophenyl)-l ,3-dihydrol -methyl-7-nitro -2- H-thieno[2,3-e][1,4]diazepin-2-one and 7-chloro-l ,3-dihydrol -methyl-5-(o-trifluoromethylphenyl)-2H-thieno[ 2,3-e][ l ,4]diazepin-2-one. Thecompounds of the'formula l above can be prepared in one prepartiveapprach by halogenating or nitrating a compound of the general formulawherein R and R are as above whereby .to provide a halogen or nitrogroup in position-7. Compounds of the formula I above can also beprepared by cyclizing a compound of the formula l a N -co-cr1 NH (Inwherein R R and R are the above.

Compounds of the formula I above wherein R is -CH X can be prepared bytreating a compound of the formula I above which is unsubstituted inposition-l; that is to say, a compound of the formula I wherein R ishydrogen, i.e. a compound of the general formula a, S" -1f (ILA)genating agent utilized in accordance with prior art procedures.

Chloroination of a compound of the formula ll above whereby to providethe corresponding compound of the formula I wherein R is chlorine can beeffected utilizing elemental chlorine, for example, in the presence ofchloroform/pyridine at room temperature or at elevated temperatures.Bromination utilizing elemental bromine can be effected, for example, inthe presence of chloroform at an elevated temperature, for example,under reflux conditions. lodination utilizing elemental iodien can beeffected, for example, in the presence of chloroform and mercuric oxideat room temperature. Chlorination utilizing sulfuryl chloride can beeffected, for example, in the presence of chloroform or glacial aceticacid at room temperature or at an elevated temperature, for example, atabout the reflux temperature of the reaction mixture.

Nitration of a compound of the formula II above can be effectedaccording to conventional procedures. For example, nitration can beeffected utilizing nitric acid or an alkali nitrate in the presence ofsulfuric acid. Thus, a compound of formula II can be dissolved inconcentrated sulfuric acid and the solution so-obtained is thereaftercarefully treated with a mixture of concentrated nitric acid andconcentrated sulfuric acid. The nitration of a compound of the formulaII above is preferably effected at low temperatures, for example at atemperature of from about lOC. to about +C.

According to a further process aspect of the present invention, thecompounds of formula 1 above can be prepared by cyclizing a compound offormula III above. The cyclization of a compound of formula III above tothe corresponding compound of the formula 1 above can be effected byheating a compound of the formula III above in an organic medium.Preferrably, the cyclization is effected in the presence of an acid. Anacid insures that satisfactory yields are obtained. Thus, thecyclization can be effected, for example, by heating a compound offormula lllabove under reflux conditions over a period of several hoursin the presence of lower aliphatic carboxylic acids such as acetic acidin a lower alkanol such as ethanol or n-propanol, or for relativelyshort periods of time (ca 5 minutes to 0.5 hour) in the presence of alower aliphatic carboxylic acid such as acetic acid, isobutyric acid orpivalic acid.

The compounds of formula III need not be isolated from the reactionmedium in which they are prepared prior to the cyclization thereof.Indeed, in certain cases, isolation thereof is quite difficult ascompounds of the formula [II above evidence the propensity tospontaneously cyelize under the conditions used for the preparationthereof.

Thus, the compounds of the formula III above can be converted tocompounds of the formula I above with or without isolation from thereaction medium in which they are prepared.

According to another process aspect of the present invention, thecompounds of formula I which are substitued in the l-position by a groupof the formula -CH -X are prepared by appropriately by substituting inthe 1-position a corresponding compound which is unsubstituted in thel-position, i.e. a compound of formula l-A.

The introduction of a group of the formula -CH -X into a compound offormula l-A can be carried out according to conventional methods. Forexample, a compound of the formula l-A above is converted into thecorresponding alkali metal derivatie thereof (for example, utilizing analkali metal lower alkoxide such as sodium methoxide, an alkali metalhydroxide such as sodium hydroxide, an alkali metal hydride such assodium hydride, an alkali metal amide such as sodium amide and the like)and thereafter reacting the so-obtained alkali metal derivative, whichneed not be isolated, with a suitable alkylating agent. For example, asuitable al kylating agent is of the formula wherein X is as above and Yrepresents a suitable leaving group.

A suitable leaving group can be represented, for example, by chlorine,bromine, iodine, alkylsulfonyloxy, e.g. methanesulfonyloxy andarylsulfonyloxy, e.g. benzensulfonyloxy, p-toluenesulfonyloxy andbromobenzenesulfonyloxy and the similar type leaving groups. A groupd ofthe formmula X-CH -SO is another suitable leaving group, especially whenX represents a hydrogen atom or lower alkyl group containing 1 to 4carbon atoms. Examples of compounds of formula IV which can be used inthis process aspect are lower alkyl halides (e.g. methyl iodide),diloweralkylsufates (e.g. dimethylsulfate) lower alkenylhalides (e.g.,allyl bromide), cycloalkylmethyl halides, (e.g.cyelopropylmethylbromide), 2-haloethanols (e.g. 2-bromoethanol),halodiloweralkyl ethers (e.g chlorodimethyl ether), dilower alkylaminolower alkyl amino halides (e.g diethylaminoethyl chloride) and the like.

The introduction of a group of the formula -CH -X is expeditiouslyeffected in the presence of an organic solvent at room temperature,preferably at a temperature of from about 0C. to about 30C. Theintroduction can be effected, for example, by adding a compound offormula l-A in the calculated amount to an alcoholic alkali metalalkoxide solution (for example, methanolic sodium methoxide solution),evaporating off the solvent, taking up the thus-obtained l-alkali metalderivative of the compound of formula l-A in a suitable inert organicsolvent (preferably a polar solvent such as dimethylformamide) andadding the alkylating agent containing the grouping CH -X which it isdesired be introduced.

The preparation of an alkali metal salt of a compound of formula l-A andthe reaction thereof with an alkylating agent can, however, as mentionedearlier, also be. carried out without isolation of the alkali metal saltderivative which is first prepared. In this preparative approach, acompound of the formula l-A above can be treated in an inert organicsolvent with an alkali metal alkoxide or an alkali metal hydride and tothe resultant reaction medium, there can be added the appropriatealkylating agent. Suitable solvents for this procedure are, for example,dimethylformamide and aromatic hydrocarbons such asbenzene, toluene andthe like. Dimethylformamide is preferably utilized as the solventmedium.

Compounds of formula I can be converted into pharmaceutically acceptableacid addition salts thereof by treatment with appropriate organic andinorganic acids. Examples of acid which form pharmaceutically acceptablesalts with compounds of the formula I above are hydrochloric acid,hydrobromic acid, sulfuric acid,

methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Compounds of the formula l above wherein R represents ahydrogen atom can be converted into alkali metal derivatives; forexample,

into sodio derivatives whereby a sodium salt can be ob- 5 tained.Included within the purview of this invention, hence are thepharmaceutically acceptable acid addition salts of a compound of theformula I in addition to Ili (XIII) (VII) I XI XVII 5 l 5 CH X SNI-PCO-CH Cl S N-COCH II I] 2 ii I] t 5 c=o c=o (m (XVIII) R5 R5 l (lCIH X ISI NHCOCH I l l [I ll i (XIV) (x1x) R R I (IlH X :NHCOCH -NH ClkfCMH -NH C=O =0 I (X I) l (XX) Having regard to the foregoing formulascheme, a nitrile of the formula V above, which can be obtained, forexample, from a corresponding aniline derivative by a Sandmeyerreaction, is converted by treatment with acetonitrile and sodium (forexample, in boiling benzene) into a compound of the formula VI abovewhich, by hydrolysis (for example, using concentrated hydrochloricacid), yields a phenacyl cyanide of formula VII above. A nitrile offormula V above can also be converted by a Grignard reaction (forexample, using methyl magnesium bromide) and subsequent hydrolysis intoa methyl ketone of the formula VIII above. A compound of the formulaVIII above can be brominated in the methyl group (for example, usingbromine in chloroform in the presence of a trace of aluminum chloride)and the soobtained compound of the formula IX above can be convertedinto a phenacyl cyanide of the formula VII above, for example, bywarming in an aqueousalcoholic potassium cyanide solution. Finally, aphenacyl bromide of the formula IX above can also be prepared from anacid chloride of the formula X above (e.g. using diazomethane andhydrogen bormide) and then, as described earlier, converted into aphenacyl cyanide of the formula VII above.

The preparation of an amino ketone of the formula XI above is carriedout by reacting a phenacyl cyanide of the formula VII above the witha-mercaptoacetaldehyde which is present in solid form dimerieally as2,5- dihydroxy-l ,4-dithiane. This reaction is carried out in thepresence of a suitable organic solvent (eg a lower alkanol such asethanol, dimethylformamide or a cyclic ether such as dioxane) and a base(eg an amine such as triethylamine, piperdine, etc.) at an elevatedtemperature (e.g. at 50100C).

Compounds of the formula XII above can be prepared by chloracetylatingan amino ketone of formula XI in accordance with conventionalprocedures; for example, the compound of the formula XI can bechloroacylated with chloroacetyl chloride in the presence of a suitablesolvent such as dioxane and a base such as postassium carbonate.

Compounds of formula XIII can be obtained by appropriately substituting(i.e. halogenating or nitrating) a compound of formula XII in the-position of the thiophene ring. This substitution can be carried out inan analogous manner to that described above in connection with thenitration or halogenation of a compound of the formula II.

In the preparation of a compound of the formulae XIV and XV above, thechlorine atom present in the side-chain of a corresponding chloroacetylcompound of the formula XII or XIII above is replaced by an iodine atom;for example, by heating a compound of the formulae XII and XIII abovewith sodium iodide in acetone (Finkelstein reaction).

Compounds of the formuale III-A and XVI above can be prepared byreplacing the iodine atom present in the side-chain of a correspondingiodoacetyl compound of the formula XV or XIV above by an amino group.Such can be effected, for example, in liquid ammonia or in a mixture ofan inert organic solvent such as methylene chloride and liquid orconcentrated aqueous ammonia. The reaction is effected over a period offrom several hours to a few days, depending upon the conditions employed.

Compounds of the formula II-A above can be prepared by cyclizing anamino compound of the formula XVI above in a manner analogous to thatdescribed above in connection with the eyclization of a compound of theformula III above to the corresponding compound of the formula I above.

Compounds of the formula II-A above can be appropriately substituted atthe nitrogen atom in the 1- position to give compounds of the formula"-8 above. The conversion of a compound of the formula ll-A above into acompound of the formula Il-B above is effected in an analogous manner asthat described above in the conversion ofa compound of the formula Iabove wherein R is hydrogen into the corresponding compound of theformula I above wherein R is -CH -X.

Compounds of formula II-B can also be prepared from the amino ketones offormula XI in the following manner:

An amino ketone is acetylated to give a compound of the formula XVIIabove which is subsequently substituted at the nitrogen atom thereofwith a group of the formula -CH X. The substitution can be effected, forexample, in an analogous manner to that described above when convertinga compound of the formula I above wherein R is hydrogen to thecorresponding compound of the formula I above wherein R is -CH X. Theacetyl group is then removed (e.g. by acid hydrolysis) from theresulting compound of formula XVIII and a carbobenzoxyglyeyl group isintroduced into the resulting compound (e.g. using carbobenzoxygylcylchloride in the presence of a base such as potassium carbonate). Thereis thus obtained a compound of formula XIX from which the carbobenzoxygroup is cleaved (e.g. by treatment with hydrogen bromide in glacialacetic acid) to give a compound of the formula XX above; however, acompound of the formula XX above is difficultly isolatable as it mayspontaneously cyclize to the corresponding compound of the formula II-Babove under the reaction conditions utilized in the preparation thereof.When X represents a hydroxymethyl group in the procedure described inthis paragraph, it may be necessary to protect the hydroxy group bymeans of a suitable protecting group and to subsequently remove theprotecting group at a suitable stage of the synthesis.

Compounds of the formula TH X (III-B) wherein R R and X have thesignificance given earlier. can also be prepared if desired, byhalogenating or nitrating any of the intermediates found in thediagrammatic flow sheet along suitable stages of the proceduresillustrated therein.

The compounds of formulae II, III, XI to XVI and XX are novel and,hence, form part of the present invention.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as muscle relaxants and sedatives. Thus, forexample, the compound 7-chloro-5- (o-chlorophenyl)-l,3-dihydro-2H-thienol2,3-e1l 1,4]- diazepin-Z-one exhibits in therotating rod test (mouse) an HD of 20 mg/kg p.o., in theantipentetrazole test (mouse) an AFR of 14 mg/kg p.o and in the test foracute toxicity (mouse) an LD of more than 5000 mg/kg p.o. In a similarmanner, the compound 7-chlorol,3-dihydro-5-(o-nitrophenyl-2H-thieno[2,3- e][1,4]diazepine-2-one exhibits in the rotating rod test (mouse) an HD of5.7 mg/kg p.o., in the antipentetrazole test (mouse), and APR of 3.3mg/kg p.o. and in the test for acute toxicity (mouse) and LD ofmore than5000 mg/kg p.o. The aforementioned tests were carried out according toknown methods.

The compounds of formula I and their pharmaceutically utilizable acidaddition salts can be compounded according to conventional proceduresinto pharmaceutical preparations, for example, tablets, dragees,suppositories, capsules, solutions, suspensions, emulsions and the like.ln addition to the customary pharmacologicaly inert carrier materials,such as, for example, lactose, starches, talc, magnesium stearate,water, vegetable oils, polyalkylene glycols and the like, thesepreparations can also contain preserving, stabilizing, wetting oremulsifying agnets, salts for varying osmotic pressure, buffers or othertherepeutically valuable substances. lf necessary, the preparations canbe sterilized or subjected to other operations which are customary inthe pharmaceutical industry.

A suitable pharmaceutical dosage unit can contain about 1 to 500 mg of acompound of the formula 1. Suitable daily dosage for oral administrationto mammals is in the range of from about 0.l mg/kg to about 300 mg/kg.For parenteral administration to mammals, a suitable daily dosage is inthe range of from about 0.1 mg/kg to about l0 mg/kg. However, it will beappreciatd that these dosages are given by way of example and thespecific dosage must be adjusted to fit the exergencies of apharmacological situation.

The following examples are illustrative but not limitative of thepresent invention. All temperatures are stated in degrees Centigrade.

EXAMPLE 1 g (0.0181 mol) of 5-(o-chlorophenyl)-l ,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved with stirring in ml ofglacial acetic and 3 ml of sulfuryl chloride are added dropwise. Themixture is then stirred for 2 hours at room temperature and neutralizedwith the calculated amount of sodium bicarbonate, whereupon theprecipitating product is filtered off with suction and washed with waterand methylene chloride. After crystallization from ethanol, there isobtained 7- chloro-5-(o-chlorophenyl)- l ,3-dihydro-2H-thieno[2,3-e][l,4]diazepin-2-one in the form of white crystals of melting point237(with decommposition).

The starting material can be manufactured as follows:

a. In a l liter three-necked flask with stirrer and dropping funnel, 112 g (0.62 mol) of o -chlorophenacyl cyanide and 47.5 g (0.62 mol) of2,5-dihydroxy-l ,4- dithiane is suspended in 600 ml of absolute ethanoland warmed to 35. 33 ml of triethylamine is then added slowly. Theresulting mixture is warmed to 55 and the reaction mixture held for 20hours at this temperature. The reaction mixture is then poured into 6 lof water and shaken up with methylene chloride. The organic phase iswashed twice with dilute hydrochloric acid, once with water, twice withdilute caustis soda and again twice with water, dried over sodiumsulfate, concentrated and brough to crystallization. The yellowish2-amino-3-(o-chlorobenzoyl)thiophene crystallizes form ethanol with theaddition of activated characoal; melting point 139-l4l.

b. g of anhydrous potassium carbonate is suspended in a solution of 100g (0.42 mol) of 2-amino-3- (o-chlorobcnzoyl) -thiophene in 500 ml ofabsolute dioxane. ml of chloroacetyl chloride is added in one portionwith strong stirring, whereupon the temperature rises. It is left tostir for 2 hours, the cooled reaction mixture is poured into a solutionof I50 g of potassium carbonate in 4 l of water and stirred for afurther 2 hours. The separated yellow solid is filtered off by suction,washed neutral with water and dried at 50 in vacuum. Afterrecrystallization from ethanol, there is obtained2-chloroacetylanino-3-(o-chlorobenzoy)thiophene in the form of yellowishcrystals of melting point l32l 34C.

c. 127.8 g (0.4 mol) of 2-chloroacetylamino-3(ochlorobenzoyl)-thiopheneand 67.5 g of sodium iodide is heated for 1 hour in acetone underreflux. The reaction mixture is then evaporated in vacuum, whereupon theresidue is partitioned between water and methylenechloride. Themethylene chloride phase is separated off, dried over sodium sulfate,concentrated and brought to crystallization. There is obtainedyellowishcolored 3-(o-chlorobenzoyl)-2- iodacetylaminothiophene whichmelts at 89-92 after crystallization form ethanol.

d. 25 g (0.06 mol) of 3-(o-chlorobenzoyl)-2- iodoacetylamino-thiopheneis dissovled in 300 ml of methylene chloride. The resultant medium iscooled to 50 and 265 ml of liquid ammonia is added to it. The mixture isstirred for 5 hours at -27C. under reflux and the ammonia is thenremoved by suction by means of a water-jet pump, whereupon the residualorganic solution is shaken up with water, dried over sodium sulfate,concentrated, treated with ether and shaken up several times with0.5-n0rmal hydrochloric acid. The hydrochloric acid phase is neutralizedwith sodium bicarbonate and shaken up several times with methylenechloride. The methylene chloride phase is dried, evaporated and broughtto crystallization yielding lightyellow2-aminoacetylamino-3-(o-chlorobenzoyl)thiophene of melting pointl58-160.

e. 106 g (0.36 mol) of 2-aminoacetylamino-3-(ochlorobenzoyl) thiopheneis'dissolved in 2.5 l of absolute ethanol. 6.5 Ml. of formic acid isthen added and the mixture is heated for 20 hours under reflux. Afterthe addition of activated charcoal, the mixture is further boiled for afurther 10 minutes, filtered and evaporated to dryness in vacuum. Thecrude product is boiled with methylene chloride, the by-products goinginto solution and 5(o-chlorophenyl)-l,3-dihydro-2H-thieno[2,3-e][l,4]diazepin-2-one remaining behind undissolved as achromatographically pure white product. the mother-liquor isconcentrated and brought to crystallization yielding further product.The product has a melting point of 222.5224.5 (after recrystallizationfrom ethanol).

EXAMPLE 2 0.0725 g (0.0025 mol) of 5-(o-chlorophenyl)-l,3-

and concentrated. The accuring oil can be brought to crystallizationwith the aid of ether. After recrystallization from cyclohexane, thereis obtained 7-chloro-5- (o-chlorphenyl) -l ,3-dihydrol-methyl-2H-thieno- [2,3-e][1,4]diazepin-2-one in the form of whitecrystals of melting point 8385.

The starting product can be manufactured as follows:

g (0.018 mol) of 5-(o-chlorophenyl)-l,3-dihydro- ZH-thieno[2,3-e][1,4]diazepin-2-one is dissolved in 18.8 ml of 1N methanolicsodium methylate solution. The resulting solution is evaporated todryness in vacuum. The residue is taken up in 29.3 ml of absolutedimethylformamide and treated with 2.64 g of methyl iodide. A clearsolution results with slight warming. After standing for 2 hours, thereaction mixture is concentrated in vacuum, treated with water andshaken up several times with methylene chloride. The organic phase isshaken up several times with 0.5-N caustic soda, washed neutral withwater, dried and evaporated. The residue is brought to crystallizationby treatment with some ether. By recrystallization from cyclohexane/ethanol, there is obtained 5-(o-chlorophenyl)-l ,3-dihydro-l-methyl-2H-thieno-[2,3-e][ 1 ,41diazepin- 2-one in the form ofwhite crystals of melting point 112-l 14.

EXAMPLE 3 thieno[2 ,3-e ][1,4-diazepin-2-one is dissolved in 30 ml ofhot abs. cholorform. 0.66 G of bromine dissolved in 30 ml of chloroformis then carefully added with stirring and with boiling at reflux. Themixture is boiled, after addition is completed, for a further minutesunder reflux. The mixture is thereafter shaken neutral with an aqueoussolution of sodium bicarbonate and sodium thiosulfate, whereupon theorganic phase is separted off, dried and evaporated. The residue isrecrystallized from ethanol, yielding7-bromo-5-(ochlorophenyl)-1,3-dihydro-2H-thieno[2,3-e][ 1,4]-

diazepin-2-one of melting point 248 (decomposition).

EXAMPLE 4 0.5 of 5-(o-chlorophenyl) l ,3-dihydro-2H- Qwettqlzfiislllflls i z a nisl s i 15 EXAMPLE 5 l 1.9 g of5-(o-fluorophenyl)-l,3-dihydro-2H- thieno[2,3-e]-[1,4]diazepin-2-onedissolved in 120 ml of glacial acetic acid is carefully added at roomtemperature with stirring to a solution of 36 m1 of sulfuryl chloride in120 ml of glacial acetic. The resulting mixture is stirred for anadditional half hour. The glacial acetic acid is thereafter distilledoff in vacuum at and the residue neutralized with a saturated sodiumhydrogen carbonate solution. The precipitate formed is filtered off,washed and dried. The brown powder obtained is extracted with boilingwith methylene chloride and recrystallized from ethanol yielding7-chloro-5-(oe][ l,4]diazepin-2-one of melting point 256259.

The starting material can be manufactured as follows:

a. 10.9 g of sodium is finely partitioned in 180 ml of boiling absolutexylene by means ofa Hershberg stirrer. After cooling, the xylene isreplaced by 300 ml of absolute benzene and the resulting medium heatedto boiling. A mixture of 27.6 g of o-fluorobenzonitrile, 20.5 g ofacetonitrile and 120 ml of absolute benzene is rapdily added dropwise insuch a way that the solution remains at a boil without further heating.It is thereafter boiled for 4 hours at reflux and stirred overnight atroom temperature. The light-brown precipitate is filtered off, washedwith absolute benzene and stirred into 300 ml of ether. Water is addedslowly to this until the precipitate dissolves and an aqueous phaseforms. The etherealphase is-separated off, dried and evaporated.o-Fluorobenzoacetodinitrile is isolated from the residue by distillationat 0.3 mm Hg and 135.

b. 22.6 G of o-fluorobenzoacetodinitrile is dissolved with shaking andcooling in ml of concentrated hydrochloric acid. The white precipitatewhich is formed after a few minutes is filtered off, washed with waterand dissolved in methylene chloride. The solution obtained is dried withsodium sulfate, filtered and evaporated yielding o-fluorophenacylcyanide of melting point 53. A further portion of o-fluorophenacylcyanide is obtained by diluting the hydrochloric acid filtrate andagitating with methylene chloride.

c. 20.9 G of o-fluorophenacyl cyanide is dissolved in 53 ml of absoluteethanol and 9.7 g of 2,5-dihydroxy- 1,4-dithiane is stirred into thissolution. 5.3 M1 of triethylamine is rapidly added dropwise withcontinued stirring in such a way that the temperature does not riseabove 50. The medium is then stirred for a further 15 hours at 50. Theresulting solution is cooled and filtered. The filtrate is stirred withactivated charcoal, filtered and taken up in the four-fold amount of l-Nhydrochloric acid and methylene chloride. The organic phase is separatedoff, washed neutral with l-N hydrochloric acid, then with water, twicewith l-N caustic soda and again with water (containing a little aceticacid). The organic solution is evaporated, whereupon the residue isdigested with as little methylene chloride as possible.2-Amino-3-(o-fluorobenzoyl)thiophene is obtained in the form oflight-yellow crystals which melt, after recrystallization from benzene,at 144-146.

d. 16.7 G of 2-amino-3-(o-fluorobenzoyl)thiophene is dissolved in ml ofabsolute dioxane, 15 g of anhydrous potassium carbonate is stirred inand 26 ml of chloroacetyl chloride is added in one portion. The mixtureis stirred for one hour at room temperature and thereafter poured into asolution of 30 g of potassium carbonate in 850 ml of water. Theseparated oil is brought to crystallization; the precipitate is filteredoff, dissolved in methylene chloride and dried with sodium sulfate. Byevaporating off the solvent, there is obtained2-ehloroacetylamino-3-(o-fluorobenzoyl)thiophene which can be used forthe further reaction as the crude product. The colorless crystals melt,after recrystallization from ethanol, at 9496.

e. 22.1 g of 2-ehloroacetylamino-3-(o-fluorobenzoyl)thiophene are boiledat reflux for one hour in 220 ml of acetone with 13.3 g of sodiumiodide. The solvent is evaporated off in vacuum, the residue partitionedbe tween methylene chloride and water containing some sodiumthiosulfate, the original phase separated off and e hane evaporated. The3-(o-fluorobenzoyl)-2- iodoacetylaminothiophene obtained can be employedin the next step without further purification. The melting point isafter recrystallization from ethanol, 149-l5 1.

f. 28.2 g of 3-(o-fluorobenzoyl)-2- iodacetylaminothiophene is dissolvedin 280 ml of methylene chloride. The solution overlaid with 280 ml ofconcentrated aqueous ammonia and stirred slowly for two and a half daysin such a way that the two layers do not intermix. The organic phase isthereafter washed neutral and extracted with 0.2-N hydrochloric acid.The hydrochloric acid solution is neutralized with sodium hydrogencarbonate and the 2- aminoacetylamino-3-(o-fluorobenzoyl)thiophene setfree is extracted with methylene chloride. After recrystallization frommethylene chloride, the colorless crystals melt at l28l29.

g. 14.3 G of 2-aminoacetylamino-3-(o-fluorobenzoyl)-thiophene are boiledat reflux for 15 minutes in 286 ml of glacial acetic acid. The glacialacetic acid is distilled off in vacuum and the residue is taken up in0.2-N hydrochloric acid and benzene. The hydrochloric acid phase iswashed several times with benzene and neutralized with sodium hydrogencarbonate, whereupon the resulting precipitate is shaken up withmethylene chloride. There is obtained 5-(o-fluorophenyl)-l ,3-dihydro-2H-thieno[2,3-e][ 1,4]diazepin-2-one of melting point of 196199.(after recrystallization from 7 EXAMPLE 6 A solution of 1.72 g of5-(2,6-difluorophenyl)-l,3- dihydro-2H-thieno[2,3-e][l,4ldiazepin-2-onein ml of glacial acetic acid is added dropwise at to a solution of 4.5ml of sulfuryl chloride in l5 ml of glacial acetic acid. After completedaddition, the resulting mixture is stirred for a further 2 hours at roomtemperature and then concentrated in vacuum. The concentrated solutionis neutralized with sodium bicarbonate solution and extracted withmethylene chloride. The methylene chloride solution is dried andevaporated. The crystalline evaporation residue consists of crude7-chloro-5-(2,6-difluorophenyl)-l ,3-dihydro-2H- thieno[2,3-e][l,4]diazepin-2-one. The product can be crystallized from ethanol ascolorless needles of melting point 245247.

The starting material can be manufactured as follows:

a. 46 G of 2',6-difluoroacetophenone is dissolved in l 10 ml of absolutechloroform and a spatula tip of anhydrous aluminum chloride is added.The resultant mixture is warmed to 40 and a solution 47 g of bromine in250 ml of absolute chloroform is added dropwise within one hour. Aftercompleted addition, the mixture is allowed to stand for a further 10minutes and then evaporated in vacuum. The residual light-brown oily2-bromo-2',6'-difluoroacetophenone is dissolved in 235 ml of ethanol andtreated with stirring with a solution of 59 g of potassium cyanide in180 ml of water. The turbid mixture is warmed to 50 and held for 1 hourat this temperature. The solution which is now clear is treated withabout 1 liter of water, stirred with activated charcoal and filtered.After it has been once more stirred with some activated charcoal andfiltered, the filtrate is acidified with cone. hydrochloric acid, thereprecipitating 2,40 ,6'-difluorophenacyl cyanide with melting point 5455.Recrystallization from ether does not raise the melting point. Byextracting T4 portion of 2,40,-difluorophanacyl cyanide can be obtained.

b. 34 G of 2',6'-dichlorophenacyl cyanide is dissolved in 80 ml ofdimethylformamide, treated with 14.5 g of 2,5-dihydroxy-l,4-dithiane and9.5 ml of triethylamine is added, the temperature rising slightly andthe 2,5-dihydroxy-l,4-dithiane going slowly into solution. The reactionmixture is stirred for 20 hours at and then poured into 1.5 liters ofwater, whereupon it is shaken up with ether. The organic phase is shakenup and stirred for 1 hour. The Z-bhloroacetylaiiiitfii-(2,6-difluorobenzoyl)thiophene accruing crystalline is filtered off,washed with water and recrystallized from ethanol; melting pointl43-l44.

d. 27 g of 2-chloroacetylamino-3-(2,6-difluorobenzoyl)-thiophene isrefluxed for 1 hour in 300 ml of absolute acetone with 14 g of sodiumiodide. The mixture is then evaporated in vacuum. The residue is takenup with water and methylene chloride and shaken with some sodiumthiosulfate, whereupon the organic phase is separated off, dried andevaporated. The residue consisting of 3-(2,6-difluorobenzoyl)-2-iodoacetylaminothiophene can be employed in the next step withoutfurther purification. After recrystallization from ethanol, its meltingpoint is l57-l59.

e. 26 G of crude 3-(2,6-d.ifluorobenzoyl)-2- iodoacetylaminothiophene isintroduced with stirring into 500 ml of liquid ammonia. The resultingmixture is refluxed for 5 hours, then evaporated to dryness in vacuumand the residue is taken up with methylene chloride and water. Theorganic phase is separated off, shaken with 0.2-N hydrochloric acid andthen treated a with so much ether that the organic phase comes to lieabove the aqueous phase, whereupon the aqueous phase is separated off.The organic phase is further shaken several times with 0.2-Nhydrochloric acid. The combined hydrochloric acid aqueous phases areneutralized with sodium bicarbonate and the precipitating2-aminoacetylamino-3-(2,6-diflu0robenzoyl)thiophene is shaken up withmethylene chloride. The methylene chloride solution is then dried andevaporated. The product can be employed in the next step without furtherpurification. After recrystallization from methanol, the melting pointis l45-l48.

f. A solution of 3.8 g of 2-aminoacetylamino-3-(2,6-difluorobenzoyl)thiophene in 76 ml of isobutyric acid is boiled atreflux for 8 minutes. The medium is then cooled and poured into sodiumbicarbonate solution, whereupon the mixture is shaken up with methylenechloride. The methylene chloride phase is separated off, shaken up with2-N hydrochloric acid and treated with so much ether that the organicphase comes to lie above the aqueous phase, whereupon the hydrochloricacid aqueous phase is separated off, the organic phase is further shakenup several times with 2-N hydrochloric acid and the combinedhydrochloric acid aqueous phases are neutralized with sodiumbicarbonate. The precipitating 5-( 2,6-dilfuorophenyl )-1,3-dihydro-2l-1- thienol2,3c-][1,4]diazepin-2-one is extracted with alarge amount of methylene chloride, whereupon the methylene chloridesolution is dried and concentrated. The crystals now precipitating arefiltered and washed with methylene chloride; melting point 235237.

EXAMPLE 7 19.5 g of 1,3-dihydro-5-(o-nitrophenyD-ZH-thieno[2,3-e][1,4]diazepin-2-one are dissolved with heating in 220 ml of100 percent glacial acetic acid. The solution is cooled and then addeddropwise over a period of 1 hour to a solution of 16 ml of sulfurylchloride in 170 ml of 100 percent glacial acetic acid, the temperaturebeing held between C. and 20C. The mixture is stirred for 1 hour andthen evaporated in vacuum, the temperature of the heating-bath notexceeding 35C. The residue is taken up with 1.3 liters of methylenechloride and 500 ml of 5 percent sodium hydrogen carbonate solutionwhich has been treated with 3 ml of concentrated ammonia. The mixture isshaken and the organic phase is separated off, shaken out with 500 ml ofsodium hydrogen carbonate solution containing 3 ml of concentratedammonia, dried over sodium sulfate, evaporated to 100 ml and left tocrystallize in an ice-box. The precipitated crystals are filtered offand digested with a little ice-cold methylene chloride. They are thenfiltered off and dried to give thin-layer chromatographically(Kieselgel/ether) pure 7-chloro-1 ,3-dihydro5-(o-nitrophenyl)-2-H-thieno[2,3-

e][ l,4]diazepin-2-one of melting point 3254C.

The starting materials can be prepared as follows:

a. 81 g of o-nitroacetophenone are dissolved in 200 ml of absolutechloroform, a spatula tip of anhydrous aluminum chloride is added and asolution of 101 g of bromine in 200 ml of absolute chloroform is addeddropwise with stirring at room temperature, decolorization and evolutionof hydrogen bromide occurring after a short period of time. After halfan hour, the addition is complete. The mixture is warmed to 50C. for 15minutes and then evaporated to dryness in a water-jet pump vacuum. Theinitially oily o-nitrophenacyl bromide is treated in the same vesselwith 380 ml of 96 percent ethanol, which causes it to crystallize out.The mixture is warmed to a temperature between 40C. and 50C. andsolution occurs. A solution of 102 g of potassium cyanide in 365 ml ofwater is added in such a way that the temperature does not exceed 60C.After stirring for 1 V2 hours at 50C. (with occasional formation of aprecipitate which goes into solution again), the mixture is diluted with2 liters of water and 50 g of activated charcoal are stirred in. Thesolid is filtered off by suction and the procedure is repeated with afurther 50 g of activated charcoal. The filtrate, which is now yellow tobrown-yellow in color, is acidified to pH 2 with concentratedhydrochloric acid and the precipitating yellow to brown-yellowcyrstalline o-nitrophenacyl cyanide is filtered off by suction andwashed twice with water and twice with a little ice-cold ethanol. Afterdrying, the product which is thus obtained is sufficiently pure forfurther use. The substance melts at 101103C.

b. 198 g of o-nitrophenacyl cyanide are dissolved in 400 ml of absolutedioxane. 79.2 g of 2,5-dihydroxy- 1,4-dithiane are suspended in thissolution and 70 ml of triethylamine are added dropwise with stirringover a period of 10 minutes, the temperature rising by 20C. and the2,5-dihydroxy-1,4-dithiane going slowly into solution. As soon as thetemperature begins to fall, the

mixture is boiled at reflux for half an hour and then evaporated in awater-jet pump vacuum. The oily residue is dissolved in 2 liters ofmethylene chloride and the solution is shaken out with two 1 literportions of 2-N hydrochlovic acid and then with three 1 liter portionsof 2-N sodium hydroxide solution. The organic phase is dried with sodiumsulfate and evaporated. 1f the oily residue does not crystallizespontaneously it is treated with ca 20 ml of methylene chloride,scratched with seed-crystals and thus brought to crystallization. Thecrystalcake is cooled to +30C. filtered off by suction as much aspossible, digested once with a little cold (3()C.) methylene chlorideand again filtered off by suction. The2-amino-3-(o-nitrobenzoyl)thiophene which is thus obtained issufficiently pure for further use. The substance melts at 114-116C.

e. 150 g of 2-amino-3-(o-nitrobenzoyl)-thiophene are dissolved in 700 mlof absolute dioxane, the solution is treated with 150 g of calcinedpotassium carbonate and 181 ml of chloroacetyl chloride are addeddropwise with stirring over a period of 30 minutes, the temperature notexceeding 60C. After the addition is complete, the mixture is stirredfor 2 hours and then poured slowly with strong stirring into 4 liters of10 percent potassium carbonate solution. The mixture is stirred for halfan hour and the product, which precipitates in large crystallinefragments, is filtered off by suction, triturated in a mortar with waterand washed thoroughly with water. After drying the 2chloroacetylamino-3-(o-nitrobenzoyl)-thiophene which is obtained meltsat 163-165. This material can be used in the next step without furtherpurification.

' d. 148 g of 2-chloroacetylamino-3-(o-nitrobenzoyl)- thiophene areboiled at reflux for 1 hour with 71 g of sodium iodide in 1.5 liters ofacetone. The mixture is then evaporated in vacuum and the residue istreated with 2 liters of methylene chloride and 2 liters of concentratedaqueous ammonia. This mixture is stirred for 48 hours in a closed vesselin such a way that the layers do not intermix. After the reaction iscomplete, the layers are separated and the aqueous phase is shaken outtwice with 200 m1 of methylene chloride. The combined organic phases arebrought to pH 7 by the addition of concentrated hydrochloric acid withstrong stirring, treated with 145 ml of concentrated hydrochloric acidand 300 ml of water, thoroughly intermixed and left to crystallizeovernight in an ice-box. The crystals are then filtered off, washed withsome methylene chloride and 0.5-N hydrochloric acid, suspended in 1liter of methylene chloride and shaken with 1 liter of 5 percent sodiumhydrogen carbonate solution and 10 ml of concentrated ammonia until theyhave gone completely into solution. The organic phase is separated offand the aqueous phase is shaken out with 200 ml of methylene chloride.The combined organic phases are dried with sodium sulfate and evaporatedto yield pure 2-aminoacetylamino-3(o-nitrobenzoyl)-thiophene of meltingpoint 184-185C.

e. g of 2-aminoacetylamino-3-(o-nitrobenzoyl)- thiophene are introducedin one portion with strong stirring into 1.5 liters of boilingisobutyric acid and the mixture is boiled at reflux for 4 minutes. It isthen cooled as rapidly as possible and decanted off from the precipitatewhich is deposited and the solution is evaporated in vacuum. Theevaporation residue and the precipitate are dissolved, with opticalwarming, in 800 ml of methylene chloride. The solution is washed neutralwith 500 ml of saturated sodium bicarbonate solution, the organic phaseis separated off and the aqueous phase is shaken out with 100 m1 ofmethylene chloride. The combined organic phases are dried with sodiumsulfate and then immediately stirred for 10 minutes with 30 g ofactivated charcoal. The sodium sulfate and the activated charcoal arethen filtered off by suction and the filtrate is shaken with 500 ml of2-N hydrochloric acid. The mixture is left overnight in an ice-box toallow l,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3- e][ l,4ldiazepin-2-one hydrochloride to crystallize out. This hydrochlorideis then filtered off, washed with some methylene chloride and 2-Nhydrochloric acid, suspended in 800 ml of methylene chloride and shakenwith 800 ml of 5 percent sodium hydrogen carbonate solution and 10 ml ofconcentrated ammonia until it has gone completely into solution. Theorganic phase is separated off and the aqueous phase is shaken out with100 ml of methylene chloride. The combined organic phases are dried withsodium sulfate and evaporated. The residue consists of crude1,3-dihydro-5-(onitrophenyl)-2l-l-thieno[2,3-e][ 1,4]diazepin-2-one.Digestion with ice-cold methylene chloride yields the pure product ofmelting point 255-257C.

EXAMPLE 8 9.14 g of 5-(o-chlorophenyl)-l,3-dihydro-2H-thieno-[2,3-e][1,4]diazepin-2-one are stirred at into 45 ml 'of cone. sulfuricacid. The resultant medium is then cooled to 10 and a mixture of 2.2 mlof nitric acid (16.45-N) and 4.7 ml of cone. sulfuric acid is addeddropwise within 25 minutes. After stirring for a further 25 minutesbetween 0 and the reaction solution is poured into ice-water andneutralized with solid sodium bicarbonate. The precipitating precipitateis filtered off, washed several times with ethanol, water and againethanol and recrystallized from dioxane yielding 5-(o-chlorophenyl)-l,3-dihydro-7-nitro-2H- thieno[2,3-e][1,4]-diazepin-2-one in the form offine yellow needles of melting point 269 (dec.)

EXAMPLE 9 0.725 g (0.0025 mol) of 5-(o-chlorophenyl)-1,3-dihydro-l-methyl-2ll-thieno[2,3-e][ 1,4]dia2epin- 2-one is dissolved at0 in 5 ml of concentrated sulfuric acid. The resultant medium is cooledto l0 and a mixture of 0.167 ml of concentrated nitric acid (D 1.42) and0.265 ml of concentrated sulfuric acid is added slowly at thistemperature. The mixture is stirred for a further 25 minutes at 5 to 0and then poured into 70 ml of sodium bicarbonate solution. Theprecipitating product is filtered off by suction and washed neutral.There is obtained 5-(o-chlorophenyl)-l ,3-dihydro-1-methyl-7-nitro-2H-thieno[2,3-e][ l ,4ldiazepin-2-one in the form of apractically pure yellow product. By rccrystallization from ethanol andbenzene with activated charcoal there is obtained a pure product ofmelting point l62l65.

EXAMPLE 10 1.5 g of 7chloro-5-(o-fluorophenyl)-l,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved with shaking in thecold in 5.5 ml of 1N methanolic sodium methylate solution. The methanolis distilled off in vacuum at room temperature. The residue is taken upin 5.5 ml of dimethylformamide 0.38 ml of methyl iodide is thereuponadded. The resultant medium is shaken until solution is complete, leftto stand for 1 hour, the dimethylformamide distilled off in vacuum andthe residue taken up in methylene chloride and 2-N caustic soda. Theorganic phase is washed with 2-N caustic soda and then with water, driedand evaporated. The

residue is boiled in cyclohexane with activated charcoal, filtered andevaporated. there being obtained 7-ch1oro-5-(o-fluorophenyl)-l,3-dihydro-l-methyl-2H-thieno[2,3-e][1,4]diazepin-2-one of melting point 9798.

EXAMPLE 11 A solution of 1.1 g of 5 (o-fluorophenyl)-l.3-dihydro-l-methyl-2H-thieno[2,3-e][1,4]diazepin- 2-one in 10 ml ofglacial acetic acid is added dropwise at room temperature and withstirring to a solution of 4 ml of sulfuryl chloride in 10 ml of glacialacetic acid. The resultant medium is further stirred for half an hourand the glacial acetic acid is thereafter distilled off in vacuum at 25.The residue is neutralized with saturated sodium bicarbonate solution,whereupon the pre cipitate is filtered off, washed and dried. Forpurification, the product is dissolved in cyclohexane, boiled withactivated charcoal, filtered and evaporated. There is obtained7-chloro-5-(o-fluorophenyl)- l ,3-dihydrolmethyl-2H-thieno[2,3-e][1,4]diazepin-2-one which is recrystallized fromcyclohexane for further purification and then melts at 9798.

The starting product can be manufactured as follows:

5.2 g of 5-(o-fluorophenyl)-l,3-dihydro-2H-thieno-[2,3-e][1,4]diazepin-2-one is dissolved in 21 m1 of l-N methanolicsodium methylate solution. The methanol is distilled off at roomtemperatur eand the residue is dried in vacuum. The product is thereupondissolved in 21 ml of dimethylformamide. 1.5 ml of methyl iodide isadded and the resultant medium is left to stand for 1 hour. Thedimethylformamide is distilled off in vacuum, whereupon the residue istaken up in methylene chloride and 2-N caustic soda. The organic phaseis separated off, washed with 2N caustic soda and water, dilute with afive-fold amount of benzene and shaken up with 2-N hydrochloric acid.The hydrochloric acid phase is separated off and neutralized with sodiumbicarbonate, whereupon the precipitate which forms is shaken up withbenzene. The benzene solution is'filtered through a column withKieselgel and then evaporated. For purification, the5-(o-fluorophenyl)-l ,3- dihydro-ZH-thieno-[2,3-e][ 1,4]diazepin-2-oneobtained is recrystallized from cyclohexane, and melts at ll3116.

EXAMPLE 12 2.4 g of 5-(o-fluorophenyl)-l,3-dihydro-2-H-thieno-[2,3-e][1,4]diazepin-2-one is dissolved in 18 ml of cone. sulfuric acidat a temperature of 5 to 0C., whereupon a mixture of 0.63 ml of 16.45-Nnitric acid and 1 ml of conc. sulfuric acid is added dropwise at -10with stirring. The mixture is further stirred for a further 30 minutesat a temperature of -5 to 0 and then poured onto 200 ml of ice-water.The separated sulfate is decomposed with sodium hydrogen carbonatesolution, whereupon the precipitate is filtered off and recrystallizedfrom ethanol. There is obtained S-(ofluorophenyl)-l,3-dihydro-7-nitro-2l-l-thieno-[ 2,3- e][ 1,4]diazepin-2-one of meltingpoint 25 8259.

EXAMPLE 13 1.1 g of 5-(o-fluorophenyl)-l,3-dihydro-l-methyl-2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved in 8 ml of cone.sulfuric acid at a temperature of 5 to 0 and then treated dropwise withstirring at 10 with a mixture of 0.27 ml of 16.45-N nitric acid and 0.5ml of cone. sulfuric acid. The mixture is further stirred for a further30 minutes at a temperature of 5 to 0 and then poured onto 100 ml ofice-water. The separated sulfate decomposed with sodium hydrogencarbonate EXAMPLE 14 1.64 g of -(o-fluorophenyl)-l,3-dihydro-7-nitro-2H- thieno[2,3-e][1,4]diazepin-2-one is dissolvedwith shaking in the cold in 6 ml of l-N methanolic sodium methylatesolution. The methanol is then distilled off in vacuum at roomtemperature and the residue is taken up in ml of dimethylformamide. 0.4ml of methyl iodide is thereupon added. The resulting mixture is shakenuntil solution is complete, left to stand for 1 hour, thedimethylformamide distilled off in vacuum and the residue taken up inmethylene chloride and 2-N caustic soda. The organic phase separatedoff, washed with 2-N caustic soda and then "with water. It is then driedand evaporated. The residue is recrystallized from benzene withactivated charcoal giving 5-(0- fluorophenyl)-l ,3-dihydrol-methyl-7-nitro-2H- thieno[2,3-e][1,4]diazepin-2-one of melting point175l77.

EXAMPLE A solution of 9.7 g ofl,3-dihydro-l-methyl-S-(ofluoromethylphenyl)-2H-thieno[2,3-e][1,4]diazepin2-one in lOO ml of glacial acetic acid is added dropwise with stirringat room temperature to a solution of 8 ml of sulfuryl chloride in 100 mlof glacial acetic acid. The mixture is stirred for 4 hours and then theglacial acetic acid is distilled off in vacuum at 25C. The residue istaken up in methylene'chloride and neutralized with sodium bicarbonatesolution. The organic phase is washed with water, dried and evaporated.The residue is recrystallized from cyclohexane with activated charcoalto yield7-chloro-1,3-dihydro-l-methyl-S-(otrifluoromethylphenyl-2H-thieno[2,3-e][1,4]diazepin-2-one of melting point 100102C.

The starting material can be prepared as follows:

15.5 g of l,3-dihydro-5-(o-trifluoromethylphenyl)-2-l-l-thieno[2,3-e][1,4]diazepin-2-one are dissolved with shaking in thecold in 55 ml of l-N methanolic sodium methylate solution. The methanolis distilled off in vacuum and the residue is taken up in 55 ml ofdimethylformamide. 3.8 ml of methyl iodide are then added and themixture is shaken until solution is complete. After 1 hour, thedimethylformamide is distilled off in vacuum and the residue is taken upin methylene chloride and water. The organic phase is shaken out withwater, dried and evaporated. The crude product is employed in the nextstep without further purification. After recrystallization for methanol,the colorless crystals of 1,3-dihydrol-methyl-5-(o-trifluoromethylphenyl)-2H- thieno[2,3-e][ l,4]diazepin-2-one melt at 110l13C.

EXAMPLE 16 0.322 g of 7-chloro-l,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved in 0.9 ml of 1.22-Nmethanolic sodium methylate solution. The resulting medium is evaporatedto dryness in vacuum and the residue is taken up with 1.8 ml of abs.

' dimethylformamide. It is thereupon treated with 0.084

lization and 7-chloro-l,3-dihydro-l-methyl-S-(onitrophenyl)2H-thieno-[2,3-e][1,4]diazepin-2-one is obtained. The product afterrecrystallization from methanol melts at 145147C.

EXAMPLE 17 0.96 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2-H-thieno[2,3-e][1,4]diazepin-2-one are dissolved in 3 ml of l-Nmethanolic sodium methylate solution. The solution is evaporated todryness in vacuum and the residue is sharply sucked dry and then takenup in 4 ml of dimethylformamide. 0.36 ml of allylbromide are added andthe flask is closed and warmed gently for 5 minutes on a water-bath. Thedimethylformamide is then evaporated off in vacuum and the residual oilis shaken out with ether and 2-N hydrochloric acid. The combined aqueoushydrochloric acid phases are washed with ether and neutralized withpotassium carbonate. The precipitating oil is shaken out several timeswith 2-N sodium hydroxide solution and dried. For the removal of ayellow coloring, it is then passed over a column (diameter 2 cm, length10 cm) of Kieselgel (diameter 0.2 0.5 mm). The eluate is evaporated andbrought to crystallization with methanol to yield 1- allyl-7-chloro-l,3-dihydro-5 o-nitrophenyl )-2-H- thieno[2,3-e][1,4]diazepin-2-one,which is recrystallized from methanol and cyclohexane and then melts at93-95C.

EXAMPLE 18 0.3 g of 2-aminoacetylamino-5-chloro-3-(2,6-difluorobenzoyl)thiophene is boiled at reflux for 8 minutes in 1 ml ofpivalic acid. The reaction mixture is then neutralized with sodiumbicarbonate solution and extracted with methylene chloride. The organicphase is treated with 2-N hydrochloric acid and then with such an amountof ether that it comes to lie above the aqueous phase and shaken upseveral times with 2-N hydrochloric acid. The combined aqueoushydrochloric acid phases are washed with ether and neutralized withsodium bicarbonate, whereupon the precipitating product is extractedwith methylene chloride and the organic phase is evaporated. The7-chloro-5-(2,6- difluorophenyl )-l ,3-dihydro-2H-thieno-[2,3-e][l,4]diazepin-2-one obtained after recrystallization from ethanolmelts at 245247.

The starting product can be manufactured as follows:

a. 3 g of 2-chloroacetylamino-3-(2,6-difluorobenzoyl)-thiophene isdissolved in 20 ml of abs. chloroform and treated with stirring with 2.2ml of sulfuryl chloride in 10 ml of chloroform. After 1 hour, themixture is washed neutral with sodium hydrogen carbonate solution. Theorganic phase is then dried and evaporated. The crystalline residue isrecrystallized from ethanol yielding 5-chloro-2-chloroacetylamino-3-(2,6- difluorobenzoyl)-thiophene of m.p. 160-163.

b. 1.5 g of 5-chloro-2-chloroacetylamino-3-(2,6-difluorobenzoyl)thiophene is dissolved in 20 ml of acetone, treated with0.75 g of sodium iodide and boiled for 1 hour at reflux. The resultingmixture is then evaporated in vacuum. The residue is taken up withmethylene chloride-water and some sodium thiosulfate is added, whereuponthe organic phase is separated off, dried and evaporated.5-Chloro-3-(2,6- difluorobenzoyl)-2-iodoacetylaminothiophene isobtained. The product after recrystallization from ethanol melts atl43145.

c. 1.4 g of 5-chloro-3-(2,6-difluorobenzoyl)-2- and then extractedseveral times with 2-N hydrochloric acid. The combined aqueoushydrochloric acid phases are washed with ether and neutralized withsodium bi-. carbonate. The precipitating product isextracted withmethylene chloride, whereupon the methylene chloride phase is dried andevaporated. 2-Aminoacetylamino-5-chloro-3-(2,6-difluorobenzoyl)thiophene is obtained.

The product after recrystallization from ether melts at EXAMPLE 19 11.12g of 5-(o-chlorophenyl)-l,3-dihydro-7-iodo- 2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved in 28.4 ml of l-N methanolicsodium methylate solution. The resultant medium is evaporated to drynessin vacuum. The residue is taken up with 50 ml of abs. dimethylformamideand then treated with 1.8 ml of methyl iodide. The solution warmssomewhat and is allowed to stand for an additional 1 hour. It is thenevaporated in vacuum, the residue is taken up with methylene chlorideand 2-N caustic soda. The organic layer is shaken up several times with2-N caustic soda and then 2-N hydrochloric acid is added. The resultantmedium is then treated with such an amount of ether that the organicphase comes to lie above the aqueous phase. The organic phase is shakenup several times with 2-N hydrochloric acid and the combinedhydrochloric acid aqueous phases are neutralized with sodiumbicarbonate. The precipitating product is extracted with ether,whereupon the ether extract is dried and evaporated. The oil whichcrystallizes immediately is recrystallized from ether yielding5-(o-chlorophenyl)-l,3-dihydro-7- iodol -methyl2 l-l -thieno[2 ,3-e][l,4Jdiazepin-2-one of m.p. 117-11s.

EXAMPLE 20 1.0 g of 5-(2,6-difluorophenyl)-l,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one is dissolved at in 7 ml of cone.sulfuric acid. The resultant solution is cooled to l0 and a mixture of0.24 ml of nitric acid (D 1.42) and 0.40 ml of cone. sulfuric acid isadded dropwise with stirring while maintaining the temperature at -10".After stirring for a further 15 minutes, the solution is poured intoice-water, neutralized with sodium bicarbonate and the precipiatingcrystals filtered off by suction. The -(2,6-difluorophenyl)-l ,3-dihydro-7-nitro-2H-thieno[2,3-e] [l,4]diazepin-2-one obtained can berecrystallized from dioxane and then melts at 268-269.

EXAMPLE 21 7.7 g of 1,3-dihydro-l -methyl-5-(o-nitrophenyl-2H- thieno[2,3-e][1,4]diazepin-2-one are dissolved in 180 ml of absolutechloroform and a solution of g of sulfuryl chloride in 20 ml of absolutechloroform is added dropwise with stirring at 20C. over a period of 20minutes. After 2/3 of the sulfuryl chloride has been added, 7-chloro-l,3-dihydrol -methyl-5-(o-nitrophenyl)-2H- thieno[2,3-E][l,4]-diazepin-2-one hydrochloride begins to precipitate out. After theaddition is complete, the mixture is stirred for 2 hours at roomtemperature and then shaken neutral with sodium bicarbonate solution,which causes everythingto go into solution. The organic phase isseparated off, dried and evaporated in vacuum. For the removal of acoloring which is adhering to the product, the evaporation residue isdissolved in 800 ml of methylene chloride and passed over a column(diameter 2 cm, length 10 cm) of Kieselgel. The column is washed with afurther 200 ml of methylene chloride and the solution is evaporated invacuum to yield 7-chlorol ,B-dihydrol -methyl5-(onitrophenyl)-2H-thieno[2,3-e][1,4]-diazepin-2-one,

which can be recrystallized from ether and then melts Uffrlf Thestarting material can be prepared as follows:

a. 10 g of 2-amino-3-(o-nitrobenzoyl)-thiophene are dissolved in 50 mlof absolute dioxane and treated with 6 g of calcined, potassiumcarbonate. 20 ml of acetyl chloride are allowed to flow, with stirring,into this mixture. After stirring for 2 hours, the mixture is pouredinto 750 ml of 10 percent potassium carbonate solution and theprecipitating product is shaken out with methylene chloride. Thesolution is dried and evaporated to yield a crystalline residue of2-acetylamino-3-(onitrobenzoyl)-thiophene, which can be recrystallizedfrom benzene and then melts at l52l53C.

b. l 1.4 g of 2-acetylamino-3-(o-nitrobenzoyl)- thiophene are dissolvedin 50 ml of absolute dioxane and 5 ml of a 20 percent sodium hydridesuspension in mineral oil are added with stirring. After the evoluationof hydrogen is complete, 5 ml of dimethyl sulfate are added and themixture is boiled at reflux for 5 minutes. It is then poured into waterand extracted several times with methylene chloride. The organic phaseis dried, stirred with activated charcoal, filtered and evaporated invacuum. The oily residue is washed several times with petroleum etherand brought to crystallization with ether. After washing with ether andbenzene, the 2-( N-acetyl-N-methylamino )-3-(o-nitrobenzoyl thiophenewhich is obtained can be recrystallized from benzene and then melts atl34-l35C.

c. 2 g of 2-(N-acetyl-N-methylamino)-3-(onitrobenzoyl) -thiophen e areheated for 10 minutes on a boiling water-bath with 10 ml of concentratedsulfuric acid. The mixture is then poured onto 250 g of ice andextracted several times with methylene chloride. The organic phase isdried, stirred with activated charcoal, filtered and evaporated invacuum. The oily residue of 2-methylamino-3-(o-nitrobenzoyl)-thiophenecan be brought to crystallization with ether. After recrystallizationfrom benzene the substance melts at l23-l24C.

d. 0.80 g of 2-methylamino-3-(o-nitrobenzoyl)- thiophene are dissolvedin 20 ml of absolutedioxane, 1.0 g of calcined potassium carbonate isadded and the mixture is treated with stirring with 1.2 g ofcarbobenzoxyglycine chloride. After stirring to 18 hours at roomtemperature, the mixture is poured into ml of 5 percent sodium hydrogencarbonate solution and extracted several times with methylene chloride.The combined organic phases are dried and evaporated. The oily residueis stirred for 30 minutes at room temperature in 5 ml of 30 percenthydrobromic acid in glacial acetic acid, then poured into 300 ml of 5percent sodium hydrogen carbonate solution and extracted several timeswith methylene chloride. The combined methylene chloride phases areshaken with 1.5-N hydrochloric acid and then with such an amount ofether that the organic phase comes to lie above the aqueous phase. Thephases are separated and the organic phase is shaken out several timeswith dilute hydrochloric 23 acid. The combined hydrochloric acid phasesare shaken out with ether and neutralized with sodium hydrogencarbonate. The precipitating product is extracted several times withmethylene chloride and the organic phase is dried and evaporated. Theoily residue is boiled at reflux for minutes in 2 ml of absolute ethanoland the resulting solution is evaporated in vacuum. The residue is takenup with ether and 0.5-N hydrochloric acid and the organic phase isextracted several times with 0.5-N hydrochloric acid. The combinedhydrochloric acid phases are stirred with activated charcoal, filteredand neutralized with sodium hydrogen carbonatejThe precipitating productis extracted with ether and the ether solution is dried, stirred withactivated charcoal, filtered and evaporated. The crystalline residueconsists of 1,3-dihydro-l-methyl-S-(onitrophenyl)-2H-thieno[2,3-e][1,4]diazepin-Z-one, which can be recrystallized from ethei and then melts at151C.

EXAMPLE 22 A solution of 8 g of l ,3-dihydro-5-(o-trifluoromethylphenyl)-2 l-l-thieno[2,3-e][1,4]diazepin-2-one in 100 ml of glacial acetic acidis added dropwise with stirring at room temperature to a solution of 4.2ml of sulfuryl chloride in 100 ml of glacial acetic acid. The mixture isstirred for 4 hours and then the glacial acetic acid is distilled off invacuum at 25C. The residue is taken up in 150 ml of methylene chlorideand neutralized with sodium bicarbonate solution. The insoluble productis filtered off, washed with methylene chloride and recrystallized fromethanol to yield 7-chloro-l,3-dihydro- 5-(o-trifluoromethylphenyl)-2H-thieno[2,3- e][l,4ldiazepin-2-one of melting point 278-28lC.

The starting material can be prepared as follows:

a. 50 g of sodium are finely partitioned in 750 ml of boiling absolutexylene using a Hershberg stirrer. After cooling, the xylene is replacedby 1250 ml of absolute benzene and the mixture is heated to boiling. Amixture of 171 g of o-trifluoromethylbenzonitrile, 90 g of acetonitrileand 500 ml of absolute benzene is rapidly added dropwise in such a waythat the solution continues to boil without further heating. It is thenboiled for 4 hours at reflux and stirred overnight at room temperature.The black precipitate is filtered off, washed with absolute benzene andstirred into 1250 ml of ether. Water is added slowly to this mixtureuntil the precipitate dissolves and an aqueous phase forms. The etherealphase is separated off, dried and evaporated. The residue is distilledat 0.01 mm Hg and 130C. and the distillate is recrystallized fromethanol to yield 0- trifluoromethylbenzoacetodinitrile of melting point7 l73C.

b. 70 g of o-trifluoromethylbenzoacetodinitrile are dissolved withshaking and cooling in 350 ml of concentrated hydrochloric acid. Afterhalf an hour, a white precipitate forms. This is then filtered off andwashed with water. A further amount of product is obtained by dilutingthe hydrochloric acid filtrate. The combined precipitates are dried andthe product is sufficiently pure for further use. Afterrecrystallization from ethanol, the colorless crystals ofo-trifluoromethylphenacyl cyanide melt at 7l-73C.

c. 61.5 g of o-trifluoromethylphenacyl cyanide are boiled at reflux forminutes in 120 ml of dioxane with 20.4 g of 2,5-dihydroxy-l,4-dithianeand 6 ml of triethylamine. The dioxane is distilled off in vacuum andthe residue is digested with the minimum amount of methylene chloride.The very pure residue consists of2-amino-3-(o-trifluoromethylbenzoyl)-thiophene,

which can be recrystallized from benzene and then melts at l29-131C.

d. 61 g of 2-amino-3-(o-trifluoromethylbenzoyl)- thiophene are dissolvedin 350 ml of absolute dioxane. 68 g of anhydrous potassium carbonate arestirred in and 68 ml of chloroacetyl chloride are added in one portion.The mixture is stirred for 2 hours at room temperature and then pouredinto a solution of 126 g of potassium carbonate in 3.5 liters of water.The precipitate which forms is filtered off and dissolved in methylenechloride. The solution is dried with sodium sulfate and the solvent isdistilled off. The crude 2- chloroacetylamino-B-(o-trifluoromethylbenzoyl thiophene is s'ufficiently'pure for furtheruse. After rccrystallization from ethanol, the substance mclts at 130-l32C.

e. 77.5 g of 2-chloroacetylamino-3-(otrifluoromethylbenzoyl)-thiopheneare boiled at reflux for 1 hour in 800 ml of acetone with 40 g of sodiumiodide. The solvent is evaporated in vacuum and the residue ispartitioned between methylene chloride and water containing some sodiumthiosulfate. The organic phase is separated off and evaporated. Thecrude 2- iodoacetylamino-3-(o-trifluoromethylbenzoyl)- thiophene whichis obtained can be employed in the next step without furtherpurification. After recrystallization from methanol, the substance meltsat 102-105C.

f. g of 2-iodoacetylamino-3-( otrifluoromethylbenzoyl)-thiophene aredissolved in 950 ml of methylene chloride. The solution is overlaid with2 A liters of concentrated aqueous ammonia and stirred slowly for 2 daysin such a way that the two layers do not intermix. The organic phase isthen washed neutral and the resulting2-aminoacctylamino-3-(otrifluoromethylbenzoyl)-thiophene is extractedwith 0.2-N hydrochloric acid, which causes the partial separation of anoily hydrochloride. The oily hydrochloride and the hydrochloric acidsolution are neutralized with sodium hydrogen carbonate and the 2-aminoacetylamino-3-(o-trifluoromethylbenzoyl)- thiophene which is setfree is extract with methylene chloride. After recrystallization frommethylene chloride, the colorless crystals melt at 178-181C.

g. 61 g of 2-aminoacetylamino-3-(otrifluoromethylbenzoyl)-thiophene areintroduced into 600 ml of boiling pivalic acid and the mixture is boiledat reflux for 30 minutes. The pivalic acid is then distilled offinvacuum and the residue is taken up in methylene chloride and neutralizedby shaking with a sodium bicarbonate solution. The sodium salt of thepivalic acid is filtered off and the organic'phase is washed with water,dried and evaporated. The residue consists ofl,3-dihydro-5-(o-trifluoromethylphenyl)-2H-thieno[2,3-e][1,4]diazepin-2-one, which is sufflciently pure for furtheruse. For purification, it is recrystallized from ethanol and then meltsat 205-207C.

EXAMPLE 23 1.0 g of 7-chloro-l,3-dihydro-5-(o-nitrophenyl)-2H- thieno[2,3-e][1,4]diazepin-2-one is dissolved in the cold in 3.2 ml of l-Nmethanolic sodium methylate solution. The methanol is distilled off invacuum and the residue is dissolved in 10 ml of dimethylformamide. 0.43g of cyclopropylmethyl bromide are added and the mixture is heated for30 minutes on a boiling waterbath. The dimethylformamide is thendistilled off in vacuum; the residue is taken up in ether and theresulting solution is shaken out with l-N sodium hydroxide solution. Theether is distilled off, the residue is dissolved in l-N hydrochloricacid and the resulting solution is washed with benzene and filtered. Thehydrochloric acid phase is neutralized with sodium bicarbonate and theoily product is taken up in methylene chloride. The solvent is distilledoff and the residual oil is chromatographed on a chromatography column(diameter 2 cm, length 30 cm) of Kieselgel (diameter 0.2 0.5 mm) usingan eluant mixture of benzene and ether (1:1 Evaporation of the eluateyields a light-yellow oil which can be brought to crystallization byscratching with methanol. After recrystallization from methanol, the7-chloro-l-cyclopropylmethyl-l,3-dihydro--(onitrophenyl)-2H-thieno[2,3-e][1,4]diazepin-2-one which isobtained melts at 9l93C.

EXAMPLE 24 0.97 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e][l,4]diazepin-2-one are dissolved in the cold in 3.15 mlof l-N methanolic sodium methylate solution. The methanol is distilledoff in vacuum, the residue is taken up in 6 ml of dimethylformamide andtreated with 0.41 g of Z-bromoethanol and the resulting mixture isheated for l hour on a boiling waterhath. The dimethylformamide is thendistilled off in vacuum and the residue is taken up in methylenechloride. The solution is shaken out with l-N sodium hydroxide solution.The methylene chloride is distilled off, the residue is dissolved in l-Nhydrochloric acid and the solution is washed with benzene and filtered.The hydrochloric acid phase is neutralized with sodium bicarbonate andthe oily product is taken up in methylene chloride. The solvent isdistilled off and the residual oil can be brought to crystallization byscratching with methanol. After recrystallization from ether, the7-chlorol ,3-dihydrol 2-hydroxyethyl)-5-(onitrophenyl)-2H-thieno[2,3-e][1,4 ]diazepin-2-one which is obtained melts at l43-l45C.

EXAMPLE 25 1.01 g of 7-ehloro-l,3-dihydro-5-(o-nitrophenyl)- 2H-thieno[2,3-e][1,4]dia2epin-2-one are treated with 3.15 ml of l-N sodiummethylate solution. The solution is evaporated to dryness in vacuum andthe residue is sharply sucked dry and then taken up in 5 mlofdimethylformamide. 0.33 g of 85 percent chlorodimethyl ether are addedand the mixture is left to stand for 2 hours at room temperature. Thesolvent is removed; the residual oil is taken up in methylene chlorideand the solution is shaken out with l-N sodium hydroxide solution. Theorganic phase is dried over sodium sulfate and evaporated to dryness.The product is brought to crystallization by the addition of a littlemethylene chloride. After recrystallization from ethanol, the 7- ehloro-1,3-dihydro-l-methoxymethyl-S-(onitrophenyl )-2H-thieno[2,3-e] 1,4]diazepin-2-one which is obtained melts at l47-149C.

EXAMPLE 26 0.96 g of 7-chloro-l,3-dihydro-5-(o-nitrophenyl)- ZH-thieno[2,3-e][1,4]diazepin-2-one are dissolved in 3 ml of l-N methanolicsodium methylate solution. The solution is evaporated to dryness invacuum and the residue is sharply sucked dry and then taken up is 4 mlof dimethylformamide. 0.5 g of freshly distilled 2- diethylaminoethylchloride are added and the flask is closed and heated for minutes on awater-bath. The dimethylformamide is then evaporated off in vacuum andthe residual oil is taken up with ether and 2-N hydrochloric acid. Theorganic phase is shaken out several times with 2-N hydrochloric acid andthe combined aqueous hydrochloric acid phases are washed with ether andneutralized with potassium carbonate. The precipitating oil is extractedseveral times with ether and the combined ether solutions are shaken outseveral times with 2-N sodium hydroxide solution, dried and evaporated.The residue is brought to crystallization with methanol. Afterrecrystallization from methanol, the7-ehloro-l-(2-diethylaminoethyl)-1.3- dihydro-S-(o-nitrophenyl)-2H-thieno[2,3- e][1,4]diazepin-2one which is obtainedmelts at l lO-l 12C.

EXAMPLE 27 l g of 7-chloro-l,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-][ 1,4]diazepin-2-one is treated with 3.1 1 ml of l-Nmethanolic sodium methylate solution. The methanol is distilled off invacuum and the residue is taken up in 8 ml of dimethylformamide. Thesolution is treated with 0.339 g of ethyl bromide and heated to C. for30 minutes on a water-bath. The dimethylformamide is then evaporated offin vacuum and the residue is dissolved in ether. The ethereal phase isshaken out several times with 0.5-N sodium hydroxide solution and thencarefully extracted with l-N hydrochloric acid. The aqueous hydrochloricacid phases are neutralized with sodium bicarbonate and shaken outseveral times with ether. The ethereal solution is dried over sodiumsulfate and evaporated. The residue consists of 7-chloro -l ,3-dihydrolethyl-5-(o-nitrophenyl)-21-1-thieno[2,3-e][l,4] diazepin-Z-Oneofmeltingpoint l67l68C., which can be recrystallized from methanol.

EXAMPLE 28 1.01 g of 7-chloro-l ,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e][1,4]diazepin-2-one are treated with 3.15 ml of l-Nsodium methylate solution and the solution is evaporated to dryness invacuum. The residue, which has been sharply filtered off by suction, istaken up in 5 ml of dimethylformamide. The solution is treated with 0.54g of isopropyl iodide, left to stand for 2 hours at room temperature andthen heated for half an hour on a water-bath. The solvent is removed andthe residual oil is taken up in ether. The solution is shaken outseveral times with 2-N hydrochloric acid. The combined hydrochloric acidphases are washed with ether, neutralized with bicarbonate and extractedseveral times with ether. The combined ether solutions are shaken outseveral times with 0.5-N sodium hydroxide solution, dried over sodiumsulfate and evaporated to dryness. The product can be brought tocrystallization by the addition of a little methanol. Afterrecrystallization from methanol, the 7-chl0ro-l,3-dihydro-lisopropyl-5-(o-nitrophenyl)-2H-thieno[2,3- e][1,4]diazepin-2-one which is obtained melts at 126l28C.

EXAMPLE 29 1.0 g of5-(2,6-difluorophenyl)-l,3-dihydro-lmethyl-2H-thieno[2,3-][1,4]diazepin-2-oneis dissolved at 0C. in 7 ml of concentrated sulfuric acid. The solutionis cooled to 10C. and treated dropwise with stirring with a mixture of0.23 ml of nitrieacid (D 1.42) and 0.37 ml of concentrated sulfuricacid, the temperature being held at l0C. After stirring for a further 15minutes, the solution is poured into icewater and neutralized withsodium bicarbonate and the precipitating light-colored crystals arefiltered off to yield 5-(2,6-difluorophenyl)-l,3-dihydro-l-methyl-7-nitro-2H-thieno-[2,3-e][1,4]diazepin-2-one which can be recrystallizedfrom dioxane and then melts at 224-225C.

The starting material can be prepared as follows:

4 g of 5-(2,6-difluorophenyl)-1,3-dihydro-2H- thieno[2,3-e][ l,4ldiazepin-2-one are dissolved in 15.3 ml of l-N methanolic sodiummethylate solution. The solution is evaporated to dryness in vacuum, theresidue is taken up with ml of absolute dimethylformamide and 2.6 g ofmethylene iodide are added. The solution warms and is left to stand for2 hours and then evaporated in vacuum. The residue is taken up withmethylene chloride and 2-N sodium hydroxide solution. The organic phaseis separated off and shaken out several times with 2-N sodium hydroxidesolution. The methylene chloride phase is then treated with 2-Nhydrochloric acid and then with such an amount of ether that it comes tolie above the aqueous phase. It is then extracted several times with 2-Nhydrochloric acid. The combined hydrochloric acid aqueous phases arewashed with ether and neutralized with sodium bicarbonate. Theprecipitated oil is extracted with ether and the ether extract is dried,filtered over Kieselgel and evaporated. The 5-(2,6-difluorophenyl)-l,3-dihydrol methyl-2H-thieno[2,3-e][ l,4]diazepin-2-one which isobtained can be recrystallized from ether and then melts at 99-l00 C.

EXAMPLE 0.9 g of 5-(2,6-difluorophenyl)-l,B-dihydro-lmethyl-2H-thieno[2,3-e][ l,4]diazepin-2-one are dissolved in25 ml of absolute chloroform and a solution of 0.8 ml of sulfurylchloride dissolved in 10 ml of chloroform is added dropwise withstirring over a period of l0 minutes. The solution is shaken out withsodium hydrogen carbonate solution, dried and evaporated. Thecrystalline residue is recrystallized from ether to yield7-chloro-5-(2,6-difluorophenyl)-l ,3-dihydro-l-methyl- 2H-thieno[2,3-e][1,4]diazepin-2-one of melting point 95-96C.

The following examples illustrate typical pharmaceutical preparationscontaining the theinodiazepine derivatives provided by the invention:

EXAMPLE A Suppositories of the following composition can be prepared:

Per Suppository 7-chloro-5-(o-ehlorophenyl)-1,3-dihydro2H-thienol2,3-e][1,4]diazepin-2-one 0.010 g cocoa butter (melting point36"37C.) 1.245 g carnauba wax 0.045 g for a suppository of L3 g Thecocoa butter and the carnauba wax are melted in a glass or steel vessel,then mixed thoroughly and cooled to 45C. Finely powdered7-chloro-5-(ochlorophenyl)-l ,3-dihydro-2H-thieno [2,3- e][l,4]diazepin-2-one is then added and the mixture is stirred until thesolid is completely dispersed. The mixture is poured into suppositorymolds of a suitable size and allowed to cool. The suppositories are thentaken out of the molds and packed individually in waxed paper or metalfoil.

EXAMPLE B Capsules of the following composition can be prepared:

thieno-[2,3-e][1,4]diazepin-2-one, the lactose and the maize starch aremixed firstly in a mixer and then in a comminuting machine. The mixtureis returned to the mixer and the tale is added and mixed thoroughly. Themixture is filled mechanically into hard gelatin capsules.

EXAMPLE C An injection solution of the following composition can beprepared:

Per Ml 7-chloro-5-(o-chlorophcnyl )-l ,3-dihydro- 5.0 mg

2H-thieno[2,3-e][ l,4ldiazepin-2-one propylene glycol 0.4 ml benzylalcohol (henzaIdehydc-lree) 0.015 ml ethanol ('71) (H0 ml sodiumbenzoate 48.8 mg henzoic acid I 2 mg water for injection q.s ad 1.0 ml

For the manufacture of 10,000 ml of an injection solution, 50 g of7-chloro-5-(o-chlorophenyl)-l ,3- dihydro-2H-thieno[2,3-e][ l,4ldiazepin-2-one are dissolved in ml of benzyl alchol and 4000 ml ofpropylene glycol and 1000 ml of ethanol are added. 12 g of benzoic acidare then dissolved in this mixture and a solution of 488 g of sodiumbenzoate in 300 ml of water for injection is added. The solution whichis obtained is brought to a volume of 10,000 ml by the addition of waterfor injection, filtered and filled into ampoules of a suitable-size; theremaining volume of the ampoules is filled with nitrogen, the ampoulesare closed by fusion and then sterilized for 30 minutes in an autoclaveat 0.7 atmosphere.

EXAMPLE D Suppositories, capsules and an injection solution whichcontain 7-chloro-l ,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e][l,4]diazepin-2-one as the active ingredient can beprepared using methods analogous to those described in Examples A, B andC respectively.

We claim:

1. A compound of the formula 7-chloro-l ,3-dihydro-S-(o-nitrophenyl)-2l-l-thieno[2,3-e][ l ,4]diazepin 2-one.

2. A compound of the formula 7-chloro-l,3-dihydrol-methyl-5-(o-nitrophenyl)-2H-thieno[2,3-

e][ 1,4 ]diazepin-2-one.

3. A compound of the formula l,3-dihydro-l -methyl-5-(o-nitrophenyl)-2H-thieno-[2,3-e][ l ,4]diazepin- 2-one.

4. A compound of the formula 1,3-dihydro-5-(onitrophenyl)-2H-thieno[2,3-e][ 1,4]diazepin-2-one.

1. A COMPOUND OF THE FORMULA 7-CHLORO-1,3-DIHYDRO-5-(ONITROPHENYL)-2H-THIENO(2,3-E)(1,4)DIAZEPIN-2-ONE.
 2. A compound of the formula 7-chloro-1,3-dihydro-1-methyl-5-(o-nitrophenyl)-2H-thieno(2,3 -e)(1,4)diazepin-2-one.
 3. A compound of the formula 1,3-dihydro-1-methyl-5-(o-nitrophenyl)-2H-thieno-(2,3-e)(1,4)diazepin-2-one.
 4. A compound of the formula 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno(2,3-e)(1,4)diazepin-2-one. 